Methotrexate, lyophilized powder for solution for injections 1000 mg - Product - ATC Classification

Rx Prescription information

METHOTREXATE-BELMED

(Information for Experts)

Trade name: Methotrexate - Belmed

International nonproprietary name: Methotrexate

Appearance: yellow to orange porous hygroscopic mass or powder, nonhomogenous in colour.

Composition: each vial / bottle contains: active substance: methotrexate - 1000 mg

excipient - 1M sodium hydroxide

Pharmaceutical form: lyophilized powder for infusion

Pharmaceutical group: Anticancer drug products. Antimetabolites.

ATC code: L01BA01.

Pharmacological characteristics

Pharmacodynamics

Methotrexate is an antimetabolite of group of structural analogues of folic acid. It acts as antineoplastic (cytostatic), immunosuppressive substance. Methotrexate inhibits dihydrofolatereductase (DHF) which transforms dihydrofolic acid in tetrahydrofolic which is a donor of single-carbon groups in synthesis of purine nucleotides and thymidylate necessary for DNA synthesis. Besides in the cell methotrexate is subjected to polyglutamation with formation of metabolites effecting inhibiting action not only to DHF but also to other folate dependent enzymes including thymidilate synthase, 5-aminoimidasole-4-carboxamide ribonucleotide (AICAR) transamilase.

Methotrexate suppresses synthesis and reparation of DNA, cellular indirect nuclear division, effects RNA and protein synthesis in less extent. It has S- phase specificity, is active relative to tissues with high proliferative activity of cells, and retards growth of malignant neoplasms. Active parting cells of tumor as well as cells of bone marrow, embryo, mucous membranes of oral cavity, intestinal tract, and urinary bladder are especially sensitive.

Pharmacokinetics

Upon intravenous administration methotrexateis quickly distributed within the volume equivalent to total volume of body liquids. The initial volume of distribution - 0.18 l/kg (18% of body weight), steady-state volume of distribution is 0.4-0.8 l/kg (40-80 % of body weight). Connection with plasma proteins is about 50 %.

Methotrexatealmost does not permeate blood-brain barrier (high concentrations are reached in liquor after intrathecal administration) when taking it in therapeutic dosage irrelevant to the mode of administration. Methotrexateis released into human milk, passes through placenta (has teratogenic action on fetus).

The substance is metabolized predominantly in hepatic cells with formation of polyglutamates (DHF inhibitors and thymidilate synthases) which can be converted into methotrexate under action of hydrolases. A little of polyglutaminated derivatives are held in the tissues for a long period. The retention time and duration of action of these active metabolites depend on type of the cells, tissue and kind of tumour. Methotrexate is insignificantly metabolized (with administration of normal doses) to 7-hydroxymethotrexate (dissolubility in water 3-5 times less than in methotrexate). Accumulation of this metabolite is carried out with administration of high doses of methotrexate, prescribed for treating osteoblastic sarcoma.

Half-life (T_1/2) of methotrexate in patients who takes less that 30 mg/m² of the preparation at the starting stage is 2-4 hours. The terminal half-life is dose-dependent and composes 3-10 hours with administration of low (less than 30 mg/m²) and 8-15 hours with administration of high doses of methotrexate (80 mg/m² and more). Methotrexate is egested mainly via kidneys by glomerular filtration and tubular release during 24 hours, less than 10 % of the substance is egested with bilis. Methotrexate clearance varies greatly and decreases with high dosage.

Egestion of the preparation in patients with frank ascites or exudates into pleural fluid is slow. With repeated administration methotrexate is accumulated in tissues in form of metabolites. Egestion of the preparation may be greatly increased with chronic renal disease.

Indications

Oncological diseases (in particular acute lymphocytic leukemia, non-Hodgkin's lymphoma (including Burkitt's lymphoma), choriocarcinoma, non- metastatic osteoblastic sarcoma).

Dosage and mode of administration

Intravenously for adult and children (stream and drop-by-drop).

The content of the vial is diluted by sterile normal saline of sodium chloride. Only single selection of the drug product from the vial is permitted and the unused solution should be utilised.

The adult dosage is determined on the grounds of body weight or body surface area. Methotrexate is applied as monotherapy or in combination with other cytostatic drug products, hormones, radiation therapy and surgical methods.

Doses and treatment regimens with methotrexate substantially differ depending on the type of disease. Calcium folinate is prescribed during treatment with high doses of methotrexate (more than 150 mg/m²) in order to protect normal cells from toxic action of the drug product. The doses of calcium folinate are determined depending on the dose of methotrexate. Up to 150 mg of calcium folinate as separate doses (by intramuscular injections, intravenous injections, infusions or orally) is usually introduced during 12-24 hours, and then 12-25 mg by intramuscular injection, intravenous injection or 15 mg orally (1theca) each 6 hours during 48 hours. The protective therapy by calcium folinate is usually started after 8-24 hours from the beginning of the infusion of methotrexate.

High-dosage treatment regimen with methotrexate:

- from 2 to 15 g/m² as 4-6 hour intravenous infusion with interval of 1-5 weeks with obligatory subsequent administration of calcium folinate that is usually started in 24 hours after starting methotrexate infusion and is administered every 6 hours in a dose 3-40 mg/m² (usually 15 mg/m²) and more depending on the concentration of methotrexate in blood serum during 48-72 hours (see above or Instruction for use of calcium folinate).

Treating patients with renal function impairment:

Methotrexate should be carefully prescribed in patients with renal function impairment. The dosage is corrected depending on creatinine clearance (with clearance >50 ml/min, the dosage reduction is not required, with clearance 20-50 ml/min, the dosage is reduced by 50 %, and with clearance <20 ml/min methotrexate should not be prescribed).

Treating patients with liver function impairment

Methotrexate should be carefully prescribed only in case of emergency in patients with significant liver function impairment (available or in past history, especially caused by alcohol abuse). Methotrexate should not be used with bilirubin level >85.5 μmol/l.

In case of hematologic disorders and impairments of liver or renal functions the dosage of the drug product should be reduced. The doses of methotrexate more than 100 mg are usually administrated by intravenous infusions with duration not more than 24 hours. Part of the dose may be administrated by primary fast intravenous injection.

Treating elderly patients

Methotrexate should be carefully used in elderly patients. Functions of liver and kidneys become worse with increase of years, moreover folate reserves are reduced, dosage reduction may be reasonable.

Side effect

Nervous system and sense organs: encephalopathy (especially in patients after brain radiation), dizziness, headache, visual impairment, drowsiness, aphasia, low-back pain, tension of nape muscles, convulsions, paralysis, hemiparesis; in separate cases - fatigue, asthenia, mental confusion, ataxia, tremor, irritation, coma; conjunctivitis, excessive blear-eyedness, cataract, photophobia, cortical blindness (with high dosage).

Cardiovascular system:rarely - pericarditis, pericardial effusion, hypotension, thromboembolic changes (arterial thrombosis, encephalitic thrombosis, deep venous thrombosis, renal vein thrombosis, thrombophlebitis, pulmonary embolism).

Hemopoietic organs and hemostasis system: anaemia, leucopenia, thrombocytopenia, neutropenia, lymphopenia (especially T- lymphocytes), hypogammaglobulinemia, hemorrhage, hematosepsis caused by leucopenia.

Respirator system: rarely - interstitial pneumonitis, pulmonary fibrosis, acerbation of pulmonary infections,

Gastrointestinal tract: gingivitis, pharyngitis, ulcerative stomatitis, anorexy, nausea, vomiting, diarrhea, dysphagia, melanorrhagia, mucosal ulceration of gastrointestinal tract, gastrointestinal hemorrhage, enteritis, liver damage, fibrosis and hepatic cirrhosis (probability is higher in patients taking continuous or long-term therapy).

Urogenital system: cystitis, nephropathy, azotemia, haematuria, hyperuricemia or expressed nephropathy, dysmenorrhea, nonstable oligospermia, oogenesis process abnormality and spermatogenesis, abnormal development of fetus.

Skin integument: dermatic erythema, intense itching, hair loss (rarely), photosensitisation, ecchymosis, acneform rash, furunculosis, ecdysis, depigmentation or hyperpigmentation, blistering, folliculitis, telangiectasia, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Allergic reactions: fever, rigor, rush, urticaria fever, anaphylaxis.

Other: immunodepression, rarely - opportunistic infection (bacterial, viral, fungal, protozoal), osteoporosis, vasculitis.

Contraindications

Hypersensitivity to methotraxate or other components of the drug product.
Significant liver function impairment (bilirubin level > 85.5 μmol/l).
Alcohol abuse.
Renal function impairment (creatinine clearance <20 ml/min).
Available disorders from hemopoietic system (in particular brain hypoplasia, leucopenia, thrombocytopenia or frank anemia).
Severe, acute disorders or chronic infections (including herpes zoster, hepatitis B or hepatitis C, tuberculosis or HIV).
Ulceration of oral cavity and gastrointestinal tract.
Pregnancy and lactation.
Live vaccine vaccination during methotrexate treatment.

Use limitations

Infection diseases, recently undergone operations, podagra or renal concrements in past history (hyperuricemia risk), myelosuppression, ulcerative colitis, ulcerative stomatitis, diarrhea, water depletion, elderly age.

Pregnancy and lactation

Methotrexate is contraindicated during pregnancy (it may cause fetal death or become a reason for congenital malformations). Men and women in child producing age should use reliable methods of contraception during methotrexate treatment and 6 months afterwards. Lactation should be stopped for the period of treatment (i.e. the drug product is released into human milk).

Overdose

Symptoms:Specified symptoms are absent. The overdose is detected by the content of methotrexate in serum.

Treatment: immediate administration of calcium foliate for neutralization of myelotoxic action of methotrexate (inward, intramuscularly or intravenously). The dose of calcium foliate should be at least equal to the dose of methotrexate, it should be administrated during the first hour; the subsequent doses are administrated as required. Hydration of organism is increased, urine alkalescence is carried out to avoid precipitation of the drug product and metabolites thereof in urine tract.

Effect on ability to drive and use other mechanisms

Taking into account possibility of emergency of such side effects as dizziness, mental confusion and drowsiness, while receiving methotrexate it is recommended to refrain from driving and using mechanisms.

Interaction with other drug products

Alcohol, hepatotoxic and hematotoxic drug products

Risk of hepatotoxic action of the drug product is increased in case of regular alcohol usage or associated receiving of other hepatotoxic drug products. With simultanoues use of Etretinate and methotrexate the concentration of the latter in blood serum may be increased and severe hepatitis may develop. Frequency of development of pancytopenia and hepatotoxic effects is increased with combination therapy by methotrexate and Leflunomide.

Antibiotics

Antibiotics for oral administration (in particular tetracyclines, chloramphenicol and antibiotics of wide action spectrum, not absorbed) may effect on enterohepatic cycle caused by inhibition of intestinal microflora or suppression of bacterial metabolism.

Such antibiotics as penicillins, glycopeptides, sulfanilamides, ciprofloxacin and cefalotin may rarely reduce renal methotrexate clearance, as a result its concentration may increase in blood serum and toxic action on hemopoietic system and intestinal tract may increase.

Probenecid, weak organic acids, pyrasol and nonsteroidal antiinflammatory drug products

Probenecid, weak organic acids (for example, loop diuretics) and pyrasol (phenylbutazone) may retard egesting of methotrexate hereupon its concentration in blood serum may increase and hematological toxicity may be increased. Risk of toxic effects also increases in case of combination usage of methotrexate in low doses and NSAID or salicylates.

Preparations having unfavourable action on brain

During associated therapy by the drug products that may cause side effects on brain (for example, sulfonamide, trimethoprim/ sulfamethoxazole, chloramphenicol, pyrimethamine) one should take into account the possibility of development of more expressed hematological disorders (in rare cases - acute pancytopenia).

Drug product causing fiolates deficiency

The toxic action of methotrexate may increase during associated therapy by the drug products that may cause fiolates deficiency (for example, sulfanilamides, trimethoprim/ sulfamethoxazole). Special care is also needed when treating patients with possessed folic acid deficiency in organism. And vice versa associated receiving of folic acid may decrease effectiveness of methotrexate therapy.

Other antirheumatic drug products

The toxic action of methotrexate usually does not increase during combination usage with other antirheumatic drug products (for example, aurum salt, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine).

Sulfasalazine

During combination usage with sulfasalazine the action of methotrexate may be potentiated as a result of suppression of synthesis of folic acid by sulfasalazine (hereupon frequency of side effects may be increased), such side effects, however, were observed only in isolated incidents.

Inhibitors of proton pomp

During concomitant usage of methotrexate and inhibitors of proton pomp (for example, omeprazole or pantoprazole) interaction may be observed. Omeprazole may reduce renal methotreaxate clearance and pantoprazole can inhibit renal elimination of metabolite 7-hydroxymethotrexate what was associated in one case with development of myalgia and tremor.

Beverages containing coffein and theophylline

During methotrexate treatment one should avoid excessive usage of beverages containing coffein and theophylline (coffee, sweet beverages, containing coffein, black tea).

Alkaloids of periwinkle may increase intracellular concentrations of methotrexate and methotreaxate polyglutamates.

Conjugated with proteins of blood serum methotrexate may be substituted by salicylates, sulfanilamides, phenytoin, tetracyclines, chloramphenicol, sulphazole, doxorubicin, cyclophosphamide and barbiturates. High level of unconjugated methotrexate in blood serum results in toxicity increase.

One should regard pharmacokinetic interaction between methotrexate and flucloxacillin (area under pharmacokinetic curve for methotrexate in blood is reduced) and 5-fluorouracil (half-life of 5-fluorouracil is increased). Significant increase of methotrexate concentration in blood serum was observed in individual cases upon usage of methotrexate along with oxacillin and omeprazole. Interaction between leflunomide and methotrexate (with development of hepatic cirrhosis, musculoskeletal infection and reduction of thrombocyte quantity) was reported. One should carefully use methotrexate in combination with immunomodulating factors during carrying out of orthopedic operations when sensitivity to introduction of infection is increased.

Methotrexate clearance may be reduced in case of concomitant usage with other cytostatic drug products.

Vitamin complexes and iron preparations for oral administration containing folic acid may change the reaction of organism to methotrexate treatment.

Special indications

While working with methotrexate one should observe common rules of working with cytostatic drug products. Working place should be covered with expendable sheets of absorbing paper with film coating on the other side. One should use protective gloves and glasses to prevent contact of the methotrexate solution with skin and eyes. In case of contact the affected area should be immediately washed with great amount of water.

Medical workers should not work with the drug product during pregnancy.

The unused solutions, instruments and materials that were in contact with methotrexate should be destroyed by burning. There is no specific recommendations on the destroy temperature.

In case of ambulatory usage one should not pour the residual matter of the drug product into drain system or throw it away along with other waste.

Precautions

Usage of methotrexate in high dosage may be very dangerous that is why high-dose therapy should be carried out only by experienced chemotherapeutists who can control concentration of methotrexate in blood serum in stationary conditions under cover of calcium folinate.

Before starting high-dose methotrexate treatment or in case of extension of therapy after break one should perform blood examination with determination of leukogram and amount of thrombocytes, level of hepatic enzymes, bilirubin, serum albumin as well as radiographic examination of thoracic organs and renal function tests. In case of clinical indications one should prescribe exclusion search of tuberculosis and hepatitis.

During therapy the patients should be under careful supervision with the purpose of timely detection of indications of possible toxic action and side effects and should be thoroughly informed on possible complications and recommended measures.

During methotrexate treatment (monthly during first 6 months and then at least every 3 months, with increasing the doses it is reasonable to increase the frequency of the examinations) the following studies are carried out:

1. Examination of oral cavity and throat to detect the changes of mucous coats.

2. Blood examination with detection of leukogram and amount of thrombocytes.

Usage of methotrexate even in normal therapeutic doses may cause suppression of hemopoietic system. Methotrexate treatment should be ceased in case of significant reduction of amount of leucocytes or trombocytes and symptomatic supporting therapy is carried out. The patients should be instructed on necessity to notify the doctor immediately on any evidences and symptoms indicating the development of infection. During associated therapy by hematotoxic drug products one should carefully watch the amount of leucocytes and trombocytes in blood.

3. Renal function tests. One should give special attention to detection of evidences of liver impairment. The treatment should not be started or should be ceased in case of insignificant deviations of the results of liver function tests or liver-biopsy. The figures are usually normalized during two weeks, and then the treatment may be continued on the doctor’s decision. Transient increase of transaminase level (2-3 times higher than the upper norm limit) in 13-20% of patients was reported. In case of stable increase of activity of liver enzymes one should reduce the doses or stop the methotrexate treatment.

4. Function renal tests and urine examination. Since methotrexate is egested mainly with urine then increase of methotrexate concentration in blood may be observed in patients with renal function impairment that may result in severe side effects. One should thoroughly control the state of patients with possible renal function impairment (elderly age). It is especially important in case of concomitant therapy by drug products that reduce excretion of methotrexate, having unfavourable effect on kidneys (in particular NSAID) or on hemopoietic system. Dehydratation may also poteniate toxic action of methotrexate.

During high-dose therapy settling of the residual matter of methotrexate or its metabolites in renal tubules is possible. In such cases maintenance of high diuresis and urine alkalescence to pH 6.5-7.0 by oral administration or administration of sodium carbonate or acetazolamide as preventive measure is recommended.

5. Respirator system examination. One should carefully watch the evidences of possible development of pulmonary function impairment and if necessary prescribe the pulmonary functions tests. Pulmonary diseases need detection and withdrawal of methotreaxte. Occurrence of corresponding symptoms (especially dry, non-productive cough) during methotrexate treatment or development of non-specific pneumonitis may indicate a potential danger of pulmonary impairment. In such cases methotrexate is ceased and the patient is thoroughly examined. Fever heat, cough with shortbreathing, hypoxemia as well as pulmonary infiltration on X-ray pictures are observed in a typical patient, with pulmonary disease caused by methotrexate usage, , though clinical picture may vary. Infection diseases should be excluded during differential exclusion. Pulmonary impairment may develop during mehtotrexate treatment in any doses.

6. If a patient has pleural exudates or ascites one should perform draining before starting methotrexate treatment. If it is not possible the therapy should not be prescribed. The methotrexate treatment should be ceased in case of development of diarrhea and ulcerative stomatitis because of high risk of development hemorrhagic enteritis and gut wall perforation.

7. It is recommended that the methotrexate treatment should be ceased one week before the surgical intervention and the therapy should be continued one or two weeks after the operation.

8. Elimination of mehtotrexate is significantly retarded with increase of body temperature (>38°C). Methotrtexate may increase risk of development of neoplasms (predominantly lymphomas). In such cases the drug product is withdrew. If no spontaneous lymphoma regression is observed then therapy with cytostatic drug products is prescribed.

9. Pregnancy should be excluded before starting the treatment.

Storage conditions

Store in protected from light place at temperature below 30^оС.

Keep away from children.

Shelf life

2 years.

Do not use after expiry of shelf life indicated on the package.

Package

1000 mg per vial or bottle. Each vial or bottle together with leaflet is placed into a box.

Pharmacy purchasing terms

On prescription.

Manufacturer